The challenge of successful design of a nucleic acid-based agent, be it ribozyme, antisense, or siRNA, for reducing the level of a disease related or other target mRNA, engages biocomplexity at many levels. One of the profound difficulties in discovering such agents for use in post-transcriptional gene silencing (PTGS) approaches is that classical molecular biology techniques, such as Western and Northern blotting, are very slow and are generally not quantitative. Further, target mRNA is folded into dense secondary and tertiary structure, may be coated with heterogeneous proteins, undergoes dynamic fluctuations in structure and resides in cells with characteristic lifetimes in intracellular compartments (nucleus, cytoplasm, ribosomes, etc.), all of which constrain the range of timescales and spatial environments available for PTGS interaction with the target mRNA. Within this milieu, target mRNA must present stable regions of accessibility for PTGS ligand interaction. Moreover, the PTGS agent must be present in the same spatial locale as the target mRNA, at sufficient concentrations to allow effective diffusion limited interaction, and in conformational state(s) that enable effective processing of target mRNA, on its proscribed time scales, for successful reduction of the target mRNA to be realized. The nature of these challenges, at both the target mRNA and PTGS agent levels, is a major factor for the slow entry of PTGS agents into the pharmaceutical market, despite their obvious potential. Thus, there is an ongoing need for methods for identifying agents that can be used to reduce the levels of a target mRNA.